Multicomponent Domino Cyclization of Ethyl Trifluoropyruvate with Methyl Ketones and Amino Alcohols as A New Way to γ-Lactam Annulated Oxazacycles

A new route to bicyclic γ-lactams was found, which was proposed as a three-component cyclization of ethyl trifluoropyruvate with methyl ketones and 1,2-, 1,3-amino alcohols. As a result, a series of trifluoromethyl-substituted tetrahydropyrrolo [2,1-b]oxazol-5-ones and tetrahydropyrrolo[2,1-b][1,3]oxazine-6-ones was synthesized, in which the substituent at the nodal carbon atom was varied. The introduction of a twofold excess of ethyl trifluoropyruvate in reactions with amino alcohols and acetone made it possible to obtain the same bicycles, but functionalized with a hydroxyester fragment, which are formed due to four-component interactions of the reagents. Transformations with 2-butanone and aminoethanol lead predominantly to similar bicycles, while an analogous reaction with aminopropanol gives N-hydroxypropyl-2,3-dihydropyrrol-5-one. Almost all bicycles are formed as two diastereomers, the structure of which was determined using 1H, 19F, 13C NMR spectroscopy, including two-dimensional experiments and XRD analysis. A domino mechanism for the formation of tetrahydropyrrolo[2,1-b]oxazacycles was proposed, which was confirmed by their stepwise synthesis through the preliminary preparation of the aldol and bis-aldol from ethyl trifluoropyruvate and methyl ketones.

Multicomponent synthesis is the most modern, simple and low-cost way to create new molecules from available starting reagents. Over the past 7 years, our group has been developing a new multicomponent approach that makes it possible to obtain various fluorine-containing heterocyclic compounds from commercially available polyfluoroalkyl-3oxo esters, methyl ketones, and nucleophiles [31][32][33][34].
This protocol is based on the outstanding ability of the polyfluoracyl group of the oxoester to attach the activated methylene group of the ketone. We have recently used this method for the synthesis of pyrrolidones annulated with an imidazole or pyrimidine ring based on the three-component reaction of ethyl trifluoropyruvate and methyl ketones with ethylenediamine or 1,3-diaminopropane [35]. It was found that, in contrast to similar The preparation of fluorine-containing tetrahydropyrrolo[2,1-b]oxazol-5-ones is limited to a few examples. Pentafluoroethyl-and tri(di)fluoromethyl-substituted derivatives were prepared by addition of CF 3 CF 2 Li to the N-valinol imide at low temperatures [21], or acid-catalyzed cyclization of phenylalaninol with methyl 5,5,5-trifluoro-4oxopentanoate [22] or ethyl 5,5-difluoro-4-oxopentanoate [23], respectively. Electrophilic fluorination of tetrahydropyrrolo[2,1-b]oxazolones via their enolation followed by the reaction with N-fluorobenzenesulfonimide at −70-(−78 • C) made it possible to synthesize such mono-fluorinated bicycles [24]. It is obvious that all these methods have strict restrictions on the reagents introduced, and some of them require special equipment. Information on fluorine-containing tetrahydropyrrolo [2,1-b][1,3]oxazine-6-ones was not found by us. Although the synthesis of fluoroorganic compounds is gaining more and more popularity [25,26], due to the unique properties [27][28][29] that fluorine atoms introduce to molecules [30], as a result, they have more prospects as biologically active substances.
Multicomponent synthesis is the most modern, simple and low-cost way to create new molecules from available starting reagents. Over the past 7 years, our group has been developing a new multicomponent approach that makes it possible to obtain various fluorine-containing heterocyclic compounds from commercially available polyfluoroalkyl-3-oxo esters, methyl ketones, and nucleophiles [31][32][33][34].
This protocol is based on the outstanding ability of the polyfluoracyl group of the oxoester to attach the activated methylene group of the ketone. We have recently used this method for the synthesis of pyrrolidones annulated with an imidazole or pyrimidine ring based on the three-component reaction of ethyl trifluoropyruvate and methyl ketones with ethylenediamine or 1,3-diaminopropane [35]. It was found that, in contrast to similar transformations of trifluoroacetoacetic ester, the use of an excess of ethyl trifluoropyruvate in the reaction with acetone and diamines under microwave irradiation leads to tricyclic products with two pyrrolidone fragments.
The formation of these products was recorded during the analysis of the reaction mixture by 19 F NMR spectroscopy and GC-MS. It should be noted that in the GC-MS analysis diastereomers of bicycles 4a and 5 had the same peaks of molecular ions, but different retention times. The use of 19 F NMR spectroscopy is very informative in such studies, since the starting pyruvate 1 (δF CF3 81.08 ppm) and products based on it have different chemical shifts of the signals of CF3 groups. The non-selective reaction of ethyl trifluoropyruvate 1 with acetone 2a and aminoethanol 3a in 1,4-dioxane prompted us to investigate this synthesis in various solvents and with different amounts of pyruvate 1. However, varying solvents (toluene, THF, dichloroethane, ethanol, acetonitrile) at equimolar loadings of reagents invariably led to the formation of a mixture of products 4a and 5, while the number of heterocycles 5 in the reaction mixture even increased (Table 1, entries 1-6).
Since bicycle 5 is the result of a four-component cyclization due to the participation of two molecules of trifluoropyruvate 1, it was logical to study these transformations with its twofold excess. Indeed, it turned out that the use of a twofold excess of pyruvate 1 increased the yield of compounds 5, while bicycle 4a was formed in a minimum amount of 2-6% (Table 1, entries 7-9). However, using an excess of pyruvate 1, we detected the formation of aldol 6a [36] and bis-aldol 7a [35] by 19 F NMR spectroscopy, which were isolated and characterized earlier. The highest yield of heterocycles 5 was achieved in THF at room temperature (Table 1, entry 9). Heating the reaction mixture in THF at 50 • C to speed up the process resulted in resinification and an increase in by-products (Table 1,  entry 10).
Thus, as a result of varying the conditions, it was found that 1,4-dioxane is the most optimal solvent for the preparation of heterocycle 4a, and THF for the synthesis of product 5.
Furthermore, we carried out three-component equimolar reactions of ethyl trifluoropyruvate 1 with methyl ketone 2a-d and 2-aminoethanol 3a or 3-amino-1-propanol 3b in 1,4-dioxane at room temperature. In this case, the introduction of aminopropanol 3b in the reaction expands the scope of these three-component transformations, allowing the synthesis of oxazine derivatives. Variation of the methyl ketone component, which used not only acetone 2a, but also 2-butanone 2b, 2-hexanone 2c, and acetophenone 2d, makes it possible to change the substituent at the nodal carbon atom of the resulting bicycles. It was found that in reactions with alkyl methyl ketones 2a-c in each case, a mixture of cisand trans-diastereomers of pyrrolo[2,1-b][1,3]oxazol-5-ones 4a-c or pyrrolo[2,1-b][1,3]oxazin-6ones 8a-c is formed (Scheme 2). Notably, there is one more regularity: trans-diastereomers were prevailed in the formation of oxazole derivatives 4, while cis-isomers were prevailed in the formation of oxazine bicycles 8.
In contrast, similar cyclizations of ethyl trifluoropyruvate 1 with amino alcohols 3a,b and acetophenone 2d in each case, lead to one diastereomer 4d c or 8d t . The change and increase in stereoselectivity of this reaction may be due to the presence of a bulky phenyl substituent, which plays the role of a conformational anchor stabilizing the most favorable diastereomeric form.
We succeeded in isolating diastereomers 4a t , 4b t , 4c c , 4d c , 8b t , 8c c , 8d t in pure form by column chromatography. Diastereomers 4a c , 4b c , 4c t , 8a c , 8a t , 8b c , 8c t , 8d t contain from 2 to 19% impurities of the second isomer, but we were able to record 13 C NMR spectra for them, in which signals of only the main compound were accumulated. The isolation of bicycles 4a t , 4b c and 8a c , 8a t , 8b c , 8b t obtained from acetone 2a and 2-butanone 2b was complicated by side products 5, 9, 10, 11, the individual synthesis of which will be described below (Schemes 3 and 4). These compounds were formed in a small amount, but strongly interfered with the separation, while no such behavior was observed in the reactions with 2-hexanone 2c. We were unable to isolate the bicycle 4a c in its pure form, and despite several column chromatography, it still contained impurities of by-products 4a t (2%) and 5 (20%). Difficulties in separating diastereomers are due to their similar physicochemical properties owing to structural similarity.
Further, reactions of a twofold excess of pyruvate 1 with acetone 2a and amino alcohols 3a,b in THF at room temperature were studied. The reaction of pyruvate 1 with acetone 2a and aminoethanol 3a leads to the formation of pyrrolo[2,1-b][1,3]oxazolone 5 functionalized with a 2-trifluoromethyl-2-hydroxypropanoate fragment (which can be called a heterocyclic aldol) as a mixture of two trans,cisand cis,cis-diastereomers in a ratio of 60%:40% (Scheme 3), which we managed to separate. Diastereomer 5 tc precipitated during the reaction, and diastereomer 5 cc was isolated from the reaction mixture by column chromatography. However, the yields of pure products are low, since fractions with an unseparated mixture of isomers remain.
19% impurities of the second isomer, but we were able to record C NMR spectra for them, in which signals of only the main compound were accumulated. The isolation of bicycles 4a t , 4b c and 8a c , 8a t , 8b c , 8b t obtained from acetone 2a and 2-butanone 2b was complicated by side products 5, 9, 10, 11, the individual synthesis of which will be described below (Schemes 3 and 4). These compounds were formed in a small amount, but strongly interfered with the separation, while no such behavior was observed in the reactions with 2-hexanone 2c. We were unable to isolate the bicycle 4a c in its pure form, and despite several column chromatography, it still contained impurities of by-products 4a t (2%) and 5 (20%). Difficulties in separating diastereomers are due to their similar physicochemical properties owing to structural similarity. , which we managed to separate. Diastereomer 5 tc precipitated during the reaction, and diastereomer 5 сc was isolated from the reaction mixture by column chromatography. However, the yields of pure products are low, since fractions with an unseparated mixture of isomers remain. The reaction of a twofold excess of pyruvate 1 with acetone 2a and aminopropanol 3b proceeds similarly and leads to the formation of a mixture of diastereomers of functionalized pyrrolo[2,1-b][1,3]oxazinone 9 in a ratio of ~ 1:1 (Scheme 3). However, due to their very similar properties, diastereomers 9 and 9' were not separated. In addition, 2-butanone 2b was introduced into interaction with a twofold excess of pyruvate 1 and amino alcohols 3a,b (Scheme 4), and unexpected results were obtained. It turned out that the use of 2-butanone 2b with pyruvate 1 and aminoethanol 3a leads to the formation of 6-methyl-substituted pyrrolo[2,1-b][1,3]oxazolone as a mixture of diastereomers 10 and 10′ in a ratio of 56%:44% by analogy with the formation of bicycles 5 and 9 (Scheme 3). In addition, N-hydroxyethylpyrrol-5-one 11a was isolated from this reaction in a small amount. In addition, 2-butanone 2b was introduced into interaction with a twofold excess of pyruvate 1 and amino alcohols 3a,b (Scheme 4), and unexpected results were obtained. It turned out that the use of 2-butanone 2b with pyruvate 1 and aminoethanol 3a leads to the formation of 6-methyl-substituted pyrrolo[2,1-b][1,3]oxazolone as a mixture of diastereomers 10 and 10′ in a ratio of 56%:44% by analogy with the formation of bicycles 5 and 9 (Scheme 3). In addition, N-hydroxyethylpyrrol-5-one 11a was isolated from this reaction in a small amount. The reaction of 2-butanone 2b with pyruvate 1 and aminopropanol 3b leads only to N-hydroxypropylpyrrol-5-one 11b as a mixture of diastereomers 11b:11b' in a ratio of 72%:28% (Scheme 4). We were able to isolate diastereomer 11b in pure form by fractional crystallization from a mixture of diethyl ether and hexane in 47% yield.
It is obvious that amino alcohols 3a,b react as mononucleophiles during the formation of pyrrolidinones 11a,b. Previously, we showed that amino alcohols 3a,b in three- The reaction of a twofold excess of pyruvate 1 with acetone 2a and aminopropanol 3b proceeds similarly and leads to the formation of a mixture of diastereomers of functionalized pyrrolo[2,1-b][1,3]oxazinone 9 in a ratio of~1:1 (Scheme 3). However, due to their very similar properties, diastereomers 9 and 9' were not separated.
In addition, 2-butanone 2b was introduced into interaction with a twofold excess of pyruvate 1 and amino alcohols 3a,b (Scheme 4), and unexpected results were obtained. It turned out that the use of 2-butanone 2b with pyruvate 1 and aminoethanol 3a leads to the formation of 6-methyl-substituted pyrrolo[2,1-b][1,3]oxazolone as a mixture of diastereomers 10 and 10 in a ratio of 56%:44% by analogy with the formation of bicycles 5 and 9 (Scheme 3). In addition, N-hydroxyethylpyrrol-5-one 11a was isolated from this reaction in a small amount.
The reaction of 2-butanone 2b with pyruvate 1 and aminopropanol 3b leads only to N-hydroxypropylpyrrol-5-one 11b as a mixture of diastereomers 11b:11b' in a ratio of 72%:28% (Scheme 4). We were able to isolate diastereomer 11b in pure form by fractional crystallization from a mixture of diethyl ether and hexane in 47% yield.
It is obvious that amino alcohols 3a,b react as mononucleophiles during the formation of pyrrolidinones 11a,b. Previously, we showed that amino alcohols 3a,b in threecomponent reactions of polyfluoroalkyl-3-oxo esters with methyl ketones 2 or cycloketones can behave both as mono-and di-nucleophiles [32,37].
The introduction of 2-hexanone 2c into the reaction with amino alcohols 3a,b and a double excess of pyruvate 1 in THF led to the formation of bicycles 4c and 8c already obtained as a mixture of diastereomers (Scheme 5). Obviously, the nucleophilicity of amethylene center of the butyl substituent in 2-hexanone 2c is significantly reduced under the influence of electronic and steric factors than in 2-butanone 2b and, therefore, does not take part in the aldol addition reaction. It can be noted that these reactions were accompanied by the formation of more by-products, compared with the reactions performed at an equimolar ratio of reagents.
Molecules 2023, 28, x FOR PEER REVIEW 7 of 24 component reactions of polyfluoroalkyl-3-oxo esters with methyl ketones 2 or cycloketones can behave both as mono-and di-nucleophiles [32,37]. The introduction of 2-hexanone 2c into the reaction with amino alcohols 3a,b and a double excess of pyruvate 1 in THF led to the formation of bicycles 4с and 8с already obtained as a mixture of diastereomers (Scheme 5). Obviously, the nucleophilicity of amethylene center of the butyl substituent in 2-hexanone 2c is significantly reduced under the influence of electronic and steric factors than in 2-butanone 2b and, therefore, does not take part in the aldol addition reaction. It can be noted that these reactions were accompanied by the formation of more by-products, compared with the reactions performed at an equimolar ratio of reagents. We were unable to select conditions for the synthesis of pyrrolo[2,1-b]oxazolones 4a,b or pyrrolo[2,1-b]oxazinones 8a,b in good yields in three-component reactions of trifluoropyruvate 1 with methyl ketones 2a,b and amino alcohols 3a,b due to the formation of side bicycles 5, 9, 10, 11, formed as a result of four-component transformations. In this regard, we used a two-stage approach through the initial preparation of aldols 6a,b from ethyl trifluoropyruvate 1 and methyl ketones 2a,b (Scheme 6), thus, aldol 6a was synthesized earlier [36], and the ethyl-substituted analog 6b was obtained for the first time. Next, aldols 6a,b were introduced into cyclization with amino alcohols 3a,b, as a result of which bicycles 4a,b and 8a,b were also obtained as a mixture of cisand trans-diastereomers. We were unable to select conditions for the synthesis of pyrrolo[2,1-b]oxazolones 4a,b or pyrrolo[2,1-b]oxazinones 8a,b in good yields in three-component reactions of trifluoropyruvate 1 with methyl ketones 2a,b and amino alcohols 3a,b due to the formation of side bicycles 5, 9, 10, 11, formed as a result of four-component transformations. In this regard, we used a two-stage approach through the initial preparation of aldols 6a,b from ethyl trifluoropyruvate 1 and methyl ketones 2a,b (Scheme 6), thus, aldol 6a was synthesized earlier [36], and the ethyl-substituted analog 6b was obtained for the first time. Next, aldols 6a,b were introduced into cyclization with amino alcohols 3a,b, as a result of which bicycles 4a,b and 8a,b were also obtained as a mixture of cis-and trans-diastereomers. Scheme 6. Two-step approach to obtaining products 4a,b and 8a,b.
We analyzed the reaction mixtures obtained by two-and three-component approaches using 19 F NMR spectroscopy. A difference in the ratio of cis-and trans-diastereomeric products 4, 8 (Table 2) was found, since the proportion of predominant isomers increased significantly. Thus, in the reactions of aldols 6a,b with aminoethanol 3a, transisomers 4a t , 4b t were formed with approximately a threefold advantage, and in reactions with aminopropanol 3b, cis-diastereomers 8a c , 8b c increased by approximately two times. This made it possible to isolate diastereomers 4a,b t and 8a,b c in higher yields. Scheme 6. Two-step approach to obtaining products 4a,b and 8a,b.
We analyzed the reaction mixtures obtained by two-and three-component approaches using 19 F NMR spectroscopy. A difference in the ratio of cisand trans-diastereomeric products 4, 8 (Table 2) was found, since the proportion of predominant isomers increased significantly. Thus, in the reactions of aldols 6a,b with aminoethanol 3a, trans-isomers 4a t , 4b t were formed with approximately a threefold advantage, and in reactions with aminopropanol 3b, cis-diastereomers 8a c , 8b c increased by approximately two times. This made it possible to isolate diastereomers 4a,b t and 8a,b c in higher yields. Heterocyclic aldols 5, 9-11, which are products of a four-component reaction, can be assumed to form in two ways: through the cyclization of bis-aldol 7 with amino alcohol 3 or through the addition of a methyl substituent of bicycles 4 and 8 to the trifluoroacyl group of pyruvate 1. However, an attempt to carry out the aldolization reaction of pyruvate 1 under the action of the bicycle 4a t was unsuccessful regardless of the conditions used (Scheme 7). While the bis-aldol 7a easily cyclized with aminoethanol 3a, giving a mixture of diastereomers of the expected heterocyclic aldols 5 tc and 5 cc with a predominance of the trans,cis-form.
Molecules 2023, 28,1983 8 of 23 assumed to form in two ways: through the cyclization of bis-aldol 7 with amino alcohol 3 or through the addition of a methyl substituent of bicycles 4 and 8 to the trifluoroacyl group of pyruvate 1. However, an attempt to carry out the aldolization reaction of pyruvate 1 under the action of the bicycle 4a t was unsuccessful regardless of the conditions used (Scheme 7). While the bis-aldol 7a easily cyclized with aminoethanol 3a, giving a mixture of diastereomers of the expected heterocyclic aldols 5 tc and 5 cc with a predominance of the trans,cis-form. The structure of the synthesized heterocycles 4, 5, 8-11 was confirmed by IR, 1 H, 19 F, 13 C NMR spectroscopy and mass spectrometry. The diastereomeric structure of bicycles 4, 5, 8, 11 was established using two-dimensional experiments 2D 1 H- 13 C HSQC, 1 H- 13 C HMBC and X-ray diffraction analysis for 4d c , 5, 8c c , 11b. All diastereomers are racemates.
The synthesized bicycles 4a-d and 8a-d contain two asymmetric centers С-6(7) and С-7a(8a) (Figure 2). Analyzing the chemical shifts of the diastereotopic protons H-A and H-B in the 1 H NMR spectra at С-7 or С-8 in heterocycles 4a-d, 8a-d, we found the following regularity: the values ΔAB = δA − δB for the alkyl-substituted heterocycles 4a-с c and 8aс c , which have the cis-configuration, are in the range ΔAB 0.41-0.56 ppm, whereas for the trans-isomers 4a-с t and 8a-с t these values are much lower, ΔAB 0.04-0.23 ppm. For diastereomers containing a phenyl substituent, the opposite pattern is observed, for example, for the cis-isomer 4d с ΔAB 0.10 ppm, while for the trans-diastereomer 8d t ΔAB 0.42 ppm (Table 3). It was found that the geminal spin-spin coupling constant of these protons of the cis-isomers 4a-d с , 8a-с с are 2 J 15.2-15.5 Hz, while for the trans-diastereomers 4a-с t , 8ad t 2 J 14.2-14. 9 Hz. Previously, we revealed similar features for the trans/cis-diastereomers of hexahydropyrrolo[1,2-a]imidazol-5-ones and hexahydropyrrolo[1,2-a]pyrimidin-6ones [35]. The synthesized bicycles 4a-d and 8a-d contain two asymmetric centers C-6(7) and C-7a(8a) (Figure 2). Analyzing the chemical shifts of the diastereotopic protons H-A and H-B in the 1 H NMR spectra at C-7 or C-8 in heterocycles 4a-d, 8a-d, we found the following regularity: the values ∆ AB = δ A − δ B for the alkyl-substituted heterocycles 4a-c c and 8a-c c , which have the cis-configuration, are in the range ∆ AB 0.41-0.56 ppm, whereas for the trans-isomers 4a-c t and 8a-c t these values are much lower, ∆ AB 0.04-0.23 ppm. For diastereomers containing a phenyl substituent, the opposite pattern is observed, for example, for the cis-isomer 4d c ∆ AB 0.10 ppm, while for the transdiastereomer 8d t ∆ AB 0.42 ppm (Table 3). It was found that the geminal spin-spin coupling constant of these protons of the cis-isomers 4a-d c , 8a-c c are 2 J 15.2-15.5 Hz, while for the trans-diastereomers 4a-c t , 8a-d t 2 J 14.2-14. 9 Hz. Previously, we revealed similar features for the trans/cis-diastereomers of hexahydropyrrolo[1,2-a]imidazol-5-ones and hexahydropyrrolo[1,2-a]pyrimidin-6-ones [35].    Some regularities were found in the shifts of the signals of trifluoromethyl group in the 19 F NMR spectra of pyrrolo[2,1-b]oxazolones 4a-d and pyrrolo[2,1-b]oxazinones 8a-d. Thus, the signals of the trifluoromethyl group of cis-isomers 4a-d c are observed in the range δ F 83.63-83.79 ppm, and the trans-forms 4a-c t in a lower field δ F 83.87-83.91 ppm, similarly for 8a-c c signals are recorded in the region δ F 83.83-83.88 ppm, and for 8a-d t at δ F 84.13-84.31 ppm.
The diastereomeric structure of pyrrolo[2,1-b]oxazol-5-one 5 tc was determined using XRD analysis (Figure 4a), conforming to which this compound is a racemic mixture of molecules having the configuration of substituents at the stereocenters С-3-R*, С-5-S*, С-9-R* according to the numbering presented in Figure 4a   A more difficult task was to determine the structure of heterocyclic aldols 5 tc , 5 cc , 9, 9' and 10, 10', which have three or four asymmetric centers, respectively.
The diastereomeric structure of pyrrolo[2,1-b]oxazol-5-one 5 tc was determined using XRD analysis (Figure 4a), conforming to which this compound is a racemic mixture of molecules having the configuration of substituents at the stereocenters C-3-R*, C-5-S*, C-9-R* according to the numbering presented in Figure 4a (Figure 4b).
For a pair of isolated diastereomers 5 tc , 5 cc (Figure 2), two-dimensional experiments 2D 1 H- 13 C HSQC and HMBC were performed, on the basis of which a complete assignment of signals in the 1 H and 13 C NMR spectra was made. The 1 H NMR spectrum of pyrrolo[2,1b]oxazol-5-one 5 tc is characterized by the presence of doublet signals of the methylene protons of the pyrrolidine ring H-7"A and H-7"B at δ H 2.99, 2.29 ppm (∆ AB 0.70 ppm, 2 J 14.9 Hz) and propanoate substituent H-1'A and H-1'B at δ H 2.63, 2.20 ppm (∆ AB 0.43 ppm, J 14.0 Hz). The 13 C NMR spectrum contains characteristic signals of carbonyl atoms at C-5" of lactam (δ C 170.2 ppm) and at C-1 of ester (δ C 167.8 ppm) fragments. The 19 F NMR spectrum contains two singlet signals of trifluoromethyl groups at δ F 83.83 and 84.92 ppm. 9-R* according to the numbering presented in Figure 4a. It was found that the hydroxyl substituent in the pyrrolidine ring and the oxygen atom of the oxazole backbone are in the trans-position, while this atom and the hydroxy group of the propanoate fragment are in the cis-position. The crystal packing of compound 5 tc is formed due to intermolecular hydrogen bonds of the lactam carbonyl and hydroxyl groups of the cycle O-2-H-2…O-1 1.816 Å and the ester carbonyl and hydroxyl group of the propanoate substituent O-4-H-4…O-5 2.054 Å (Figure 4b).
(a) (b) For a pair of isolated diastereomers 5 tc , 5 cc (Figure 2), two-dimensional experiments 2D 1 H- 13 C HSQC and HMBC were performed, on the basis of which a complete assignment of signals in the 1 H and 13   According to 1 H, 19 F and 13 C NMR spectra, diastereomer 5 cc has a similar set of characteristic signals. However, analyzing the 1 H NMR spectrum, it was found that the doublet signals of the methylene protons of the cycle at H-7"A and H-7"B (δ H 2.61, 2.26 ppm) have a lower value ∆ AB 0.35 ppm and a smaller J constant of 14.0 Hz compared to the analogous values of the 5 tc heterocycle. It is obvious that for diastereomers 5 tc , 5 cc , containing a hydroxypropanoate fragment, the same trend in changing ∆ AB and constant J is observed, as for bicycle 4d c , which has a bulky phenyl substituent. For the methylene protons H-1'A and H-1'B of the propanoate residue, resonating as doublet signals at δ H 2.67, 2.50 ppm, the value of ∆ AB 0.17 ppm and J 15.0 Hz also changes. In the 13 C NMR spectra of the 5 tc and 5 cc isomers, the largest differences in shifts were recorded for the carbon atoms C-7" (δ C 42.1, 44.6 ppm) of the pyrrolidine ring and C-1 (δ C 37.8, 40.8 ppm) of the propanoate substituent, which are adjacent to the C-7" and C-2 stereocenters (Figure 2). All these data allow us to suggest that the 5 cc bicycle has a cis,cis-diastereomeric structure, in which the position of the substituents at the C-7" and C-2 stereocenters changes compared to the 5 tc isomer.
The structure of pyrrolo[2,1-b][1,3]oxazin-6-ones 9, 9' and pyrrolo[2,1-b]oxazol-5-ones 10, 10' was also established using 1 H, 13 C and 19 F NMR spectra, which contained a double set of all signals, since we were unable to separate diastereomers of bicycles 9 and 10. However, their spectra characteristics were similar to those of bicycles 5 tc and 5 cc , that allowed us to assign them a similar structure, but without determining the diastereomeric structure due to close values of the chemical shifts of protons and carbon atoms in the 1 H and 13 C NMR spectra (see the experimental part).
To establish the diastereomeric structure of dihydropyrrol-5-ones 11a,b, which have two asymmetric centers C-2 and C-4" (Figure 5), we used the data of 1 H, 13 C NMR spectroscopy and XRD analysis performed for 11b. For compounds 11a and 11b, twodimensional 2D 1 H- 13 C HSQC and HMBC experiments were carried out, on the basis of which a complete assignment of signals in the 1 H and 13 C NMR spectra was made. According to 1 H, 19 F and 13 C NMR spectra, diastereomer 5 сc has a similar set of characteristic signals. However, analyzing the 1 H NMR spectrum, it was found that the doublet signals of the methylene protons of the cycle at H-7''A and H-7''B (δH 2.61, 2.26 ppm) have a lower value ΔAB 0.35 ppm and a smaller J constant of 14.0 Hz compared to the analogous values of the 5 tc heterocycle. It is obvious that for diastereomers 5 tc , 5 сc , containing a hydroxypropanoate fragment, the same trend in changing ΔAB and constant J is observed, as for bicycle 4d c , which has a bulky phenyl substituent. For the methylene protons H-1'A and H-1'B of the propanoate residue, resonating as doublet signals at δH 2.67, 2.50 ppm, the value of ΔAB 0.17 ppm and J 15.0 Hz also changes. In the 13 C NMR spectra of the 5 tc and 5 cc isomers, the largest differences in shifts were recorded for the carbon atoms С-7'' (δC 42.1, 44.6 ppm) of the pyrrolidine ring and С-1 (δC 37.8, 40.8 ppm) of the propanoate substituent, which are adjacent to the C-7'' and C-2 stereocenters (Figure 2). All these data allow us to suggest that the 5 cc bicycle has a cis,cis-diastereomeric structure, in which the position of the substituents at the C-7'' and C-2 stereocenters changes compared to the 5 tc isomer.
The structure of pyrrolo[2,1-b][1,3]oxazin-6-ones 9, 9' and pyrrolo[2,1-b]oxazol-5ones 10, 10' was also established using 1 H, 13 C and 19 F NMR spectra, which contained a double set of all signals, since we were unable to separate diastereomers of bicycles 9 and 10. However, their spectra characteristics were similar to those of bicycles 5 tc and 5 cc , that allowed us to assign them a similar structure, but without determining the diastereomeric structure due to close values of the chemical shifts of protons and carbon atoms in the 1 H and 13 C NMR spectra (see the experimental part).
To establish the diastereomeric structure of dihydropyrrol-5-ones 11a,b, which have two asymmetric centers C-2 and C-4'' ( Figure 5), we used the data of 1 H, 13 C NMR spectroscopy and XRD analysis performed for 11b. For compounds 11a and 11b, two-dimensional 2D 1 H- 13 C HSQC and HMBC experiments were carried out, on the basis of which a complete assignment of signals in the 1 H and 13 C NMR spectra was made. The diastereomeric structure of dihydropyrrol-5-one 11b was determined by X-ray diffraction data (Figure 6a). Crystal packing is formed of a racemic mixture of molecules linked by intermolecular hydrogen bonds O-1-H-1…O-2 1.882 Å, O-3-H-3…O-6 2.122 Å (Figure 6b). The configuration of the substituents in the pyrrole ring at the С-1 stereocenter is R*, and that of the propanoate substituent at С-8 is S* (numbering is used according to The diastereomeric structure of dihydropyrrol-5-one 11b was determined by X-ray diffraction data (Figure 6a). Crystal packing is formed of a racemic mixture of molecules linked by intermolecular hydrogen bonds O-1-H-1 . . . O-2 1.882 Å, O-3-H-3 . . . O-6 2.122 Å (Figure 6b). The configuration of the substituents in the pyrrole ring at the C-1 stereocenter is R*, and that of the propanoate substituent at C-8 is S* (numbering is used according to X-ray diffraction data, Figure 6). The 13 C NMR spectra analysis of dihydropyrrol-5-ones 11b and 11b' revealed the presence of two downfield signals at δС 113.0-113.5 ppm and δС 137.1-138.4 ppm, which correspond to two sp 2 -hybridized carbon atoms C-3'' and C-2'', respectively.
In the 19 F NMR spectra of diastereomers 11b and 11b', the signals of the trifluoromethyl group of the pyrrole cycle (δF 85.74, 85.81 ppm) and the propanoate substituent (δF 85.81, 86.01 ppm) are observed in approximately the same range. However, according to the 1 H NMR spectra, the nature of the signals of the methylene protons H-1' of the propanoate fragment of isomers 11b and 11b' differs, which may indicate a different configuration of substituents at the adjacent C-2 stereocenter. Thus, the protons H-1'A and H-1'B in the spectrum of isomer 11b resonate as two doublets at δH 3.19 and 2.97 ppm (ΔAB 0.22 ppm, J 14.9 Hz), while the signals of the same protons of isomer 11b' are observed as an AB system at δH 3.08 ppm (JAB 16.7 Hz, ΔAB 0.1 ppm). Taking into account that, according to X-ray diffraction analysis (Figure 6), the substituents at the С-2 stereocenter in diastereomer 11b have the S*-configuration. The difference in the nature of the resonation of the protons of the neighboring methylene group C-1' allows us to assume the opposite R*configuration for the 11b' isomer ( Figure 5).
The 13 C NMR spectrum of pyrrolone 11а also contained characteristic low-field signals C-3'' (δС 113.37 ppm) and C-2'' (δС 137.90 ppm), confirming the presence of a double bond in the molecule. In its 1 H NMR spectrum, methylene protons H-1' resonate as a singlet at δH 3.16 ppm, which can be a degenerate AB system with ΔAB 0 ppm, which is closer in nature to the signals of similar protons of isomer 11b' (AB-system at δ 3.08 ppm, ΔAB 0.1 ppm). Based on this, we assumed that compound 11a has the R*-configuration of substituents at C-2 ( Figure 5).
Considering the mechanism of formation of bicycles 4a-d and 8a-d from ethyl trifluoropyruvate 1, methyl ketones 2a-d and amino alcohols 3a,b, it can be safely assumed that three-component cyclizations are a sequential domino process (Scheme 8). The first stage of which is aldolization, since by optimizing the conditions for the reaction of pyruvate 1 with acetone 2a and aminoethanol 3a (Scheme 1, Table 1), we detected aldol 6a. The 13 C NMR spectra analysis of dihydropyrrol-5-ones 11b and 11b' revealed the presence of two downfield signals at δ C 113.0-113.5 ppm and δ C 137.1-138.4 ppm, which correspond to two sp 2 -hybridized carbon atoms C-3" and C-2", respectively.
In the 19 F NMR spectra of diastereomers 11b and 11b', the signals of the trifluoromethyl group of the pyrrole cycle (δ F 85.74, 85.81 ppm) and the propanoate substituent (δ F 85.81, 86.01 ppm) are observed in approximately the same range. However, according to the 1 H NMR spectra, the nature of the signals of the methylene protons H-1' of the propanoate fragment of isomers 11b and 11b' differs, which may indicate a different configuration of substituents at the adjacent C-2 stereocenter. Thus, the protons H-1'A and H-1'B in the spectrum of isomer 11b resonate as two doublets at δ H 3.19 and 2.97 ppm (∆ AB 0.22 ppm, J 14.9 Hz), while the signals of the same protons of isomer 11b' are observed as an AB system at δ H 3.08 ppm (J AB 16.7 Hz, ∆ AB 0.1 ppm). Taking into account that, according to X-ray diffraction analysis (Figure 6), the substituents at the C-2 stereocenter in diastereomer 11b have the S*-configuration. The difference in the nature of the resonation of the protons of the neighboring methylene group C-1' allows us to assume the opposite R*-configuration for the 11b' isomer ( Figure 5).
The 13 C NMR spectrum of pyrrolone 11a also contained characteristic low-field signals C-3" (δ C 113.37 ppm) and C-2" (δ C 137.90 ppm), confirming the presence of a double bond in the molecule. In its 1 H NMR spectrum, methylene protons H-1' resonate as a singlet at δ H 3.16 ppm, which can be a degenerate AB system with ∆ AB 0 ppm, which is closer in nature to the signals of similar protons of isomer 11b' (AB-system at δ 3.08 ppm, ∆ AB 0.1 ppm). Based on this, we assumed that compound 11a has the R*-configuration of substituents at C-2 ( Figure 5).
Considering the mechanism of formation of bicycles 4a-d and 8a-d from ethyl trifluoropyruvate 1, methyl ketones 2a-d and amino alcohols 3a,b, it can be safely assumed that three-component cyclizations are a sequential domino process (Scheme 8). The first stage of which is aldolization, since by optimizing the conditions for the reaction of pyruvate 1 with acetone 2a and aminoethanol 3a (Scheme 1, Table 1), we detected aldol 6a. In addition, we also experimentally demonstrated the feasibility of cyclization of al- dols 6a,b with amino alcohols 3a,b into bicycles 4a,b and 8a,b (Scheme 7), presumably proceeding through the condensation of the keto group of aldol 6 with the amino group of amino alcohol 3 leading to intermediate X1, which after tautomerization undergoes intramolecular cyclization involving ester and amino groups, providing dihydropyrrol-5one X2. At the last stage, the formation of the second cycle occurs due to the intramolecular addition of a hydroxyl group to the double bond.
Similar processes can be assumed for the four-component formation of heterocyclic aldols 5 and 9, only the stage of formation of bis-aldol 7 is added, which then cyclizes with amino alcohol 3 (Scheme 8), forming dihydropyrrol-5-one X4. Such compounds were isolated and characterized in the case of Me-substituted derivatives 11a,b. Subsequent intramolecular cyclization of pyrrolones X4 gives bicyclic products 5, 9, 10.

Material
The solvents (acetonitrile, chloroform, hexane, diethyl ether and acetone 2a) were obtained from AO "VEKTON" (St. Petersburg, Russia). 2-Butanone 2b, 2-hexanone 2c, 3- In addition, we also experimentally demonstrated the feasibility of cyclization of aldols 6a,b with amino alcohols 3a,b into bicycles 4a,b and 8a,b (Scheme 7), presumably proceeding through the condensation of the keto group of aldol 6 with the amino group of amino alcohol 3 leading to intermediate X1, which after tautomerization undergoes intramolecular cyclization involving ester and amino groups, providing dihydropyrrol-5one X2. At the last stage, the formation of the second cycle occurs due to the intramolecular addition of a hydroxyl group to the double bond.
Similar processes can be assumed for the four-component formation of heterocyclic aldols 5 and 9, only the stage of formation of bis-aldol 7 is added, which then cyclizes with amino alcohol 3 (Scheme 8), forming dihydropyrrol-5-one X4. Such compounds were isolated and characterized in the case of Me-substituted derivatives 11a,b. Subsequent intramolecular cyclization of pyrrolones X4 gives bicyclic products 5, 9, 10.

General Procedures
Synthesis of compounds 4 and 8 (method A): A solution of ethyl trifluoropyruvate 1 1530 mg (9 mmol) and methyl ketone 2a-d (9 mmol) in 1,4-dioxane (5 mL) was placed in a flat-bottomed flask. Then, amino alcohol 3a,b (9 mmol) was added. The reaction mixture was stirred for 3-7 days at room temperature (25 • C). After completion of the reaction (TLC and NMR 19 F monitoring), the reaction mixture was concentrated on a rotary evaporator. The residue was triturated with hexane, and the resulting precipitate was collected by filtration and purified by recrystallization from an appropriate solvent (MeCN, Et 2 O), or by column chromatography (eluent: CHCl 3 , CHCl 3 -Et 2 O/1:1).
Synthesis of products 4 and 8 (method C): A solution of aldol 6a,b (5 mmol) in 1,4dioxane (3 mL) was placed in a flat-bottomed flask. Then the amino alcohol 3a,b (5 mmol) was added. The reaction mixture was stirred at room temperature (25 • C) for 4-5 days. After completion of the reaction (TLC and 19 F NMR monitoring), the reaction mixture was concentrated on a rotary evaporator, the residue was purified by column chromatography (eluent: CHCl 3 -Et 2 O/1:1).
Synthesis of compounds 5 (method D): A solution of bis-aldol 7a (1990 mg, 5 mmol) in THF (3 mL) was placed in a flat-bottomed flask. Then the amino alcohol 3a (305 mg, 5 mmol) was added. The reaction mixture was stirred at room temperature (25 • C) for 4-5 days. After completion of the reaction (TLC and 19F NMR monitoring), the reaction mixture was concentrated on a rotary evaporator, the residue was purified by column chromatography (eluent: CHCl 3 -Et 2 O / 1:1). Product 5 tc precipitated out during the reaction. The precipitate was filtered and purified by recrystallization from MeCN. The filtrate was evaporated, purified by column chromatography (eluent CHCl 3 -Et 2 O/2:1), product 5 cc was obtained.  13 C NMR (126 MHz, DMSO-d 6 ) δ 13.9 (C-4'), the introduction of various substituents at the nodal carbon atom of these bicycles. The method proposed by us is distinguished by the simplicity of execution and the availability of initial reagents.
It has been shown that the structure of final γ-lactams is determined by the stoichiometric amount of ethyl trifluoropyruvate and the nature of methyl ketone. At the same time, distinctive features of the transformations of amino alcohols were found in comparison with the previously studied reactions with 1,2-, 1,3-diamines, since the use of a double excess of ethyl trifluoropyruvate results in the formation of bicyclic aldols rather than tricyclic dipyrrolooxazacycles [35]. This feature is due to the fact that the oxygen atom in the cycle does not have the opportunity for subsequent addition reactions, and, consequently, the formation of tricycles. In addition, the reaction of a double excess of pyruvate with 2-butanone and aminopropanol stops at the stage of formation of N-hydroxypropyl-2,3dihydropyrrol-5-one, the possibility of its isolation is probably due to the lower reactivity of the hydroxyl group compared to the amino function. It can also be noted that, in contrast to the transformations of diamines, three-component cyclizations with amino alcohols are less diastereoselective, since they predominantly lead to the formation of two cisand trans-isomers, the diastereomeric structure of which we were able to reliably establish using NMR spectroscopy and X-ray diffraction.
The mechanism of formation of bicyclic γ-lactams has been determined. It represents successive domino reactions with the initial formation of an aldol and a bis-aldol from pyruvate and methyl ketone, which becomes possible due to the increased electrophilicity of the carbonyl group at the trifluoromethyl substituent.